Assembly-dependent endocytosis and clearance of extracellular a-synuclein

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…Conflicting data have been presented for tau, α-synuclein, and huntingtin peptides. α-synuclein uptake reportedly occurs via a temperature-sensitive mechanism that can be blocked by inhibiting endocytosis with a dominant negative dynamin mutant [32,33,64]. Proteinase K, which removes proteins from the extracellular surface, also abolishes the majority of α-synuclein uptake from the media [64].…”

“…This is consistent with a receptor-mediated mechanism. While the post-endocytic trafficking of α-synuclein is not yet clear, lysosomal inhibition with Bafilomycin A increases the levels of accumulated α-synuclein in the acceptor cell population [33,64]. Thus, the internalized α-synuclein may be degraded via lysosomes.…”

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

“…Cellmediated clearance pathways including endocytosis or phagocytosis have been reported to clear extracellular α-syn. 17 Immunization against α-syn can improve α-syn pathology, possibly due to increased cell-mediated clearance. 89,90 As Additionally, plasmin in the CNS is physiologically and pathologically important in such as neuronal development, synaptic plasticity and excitotoxicity through the cleaving of extracellular matrix components such as fibronectin, laminin and MMPs in addition to fibrin.…”

“…[15][16][17][18] Although the exact mechanism of α-syn uptake has not been established, 11-amino acid imperfect repeats found in the α-syn sequence have been shown to be critical. 16 α-Syn has been shown to be internalized via GM1 and hitherto unknown protein receptors via a lipid raft-dependent endocytosis mechanism, 18 suggesting that cytosolic α-syn can be released from cells and taken up by other cells.…”

Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

“…In recipient cells, internalization of extracellular α -synuclein aggregates may occur through endocytosis of the free protein or through direct fusion of exosomes to the plasma membrane. The transferred α -synuclein is thought to move through the endolysosomal pathway and to be degraded in lysosomes (Lee et al , 2008 ). However, under conditions of compromised lysosomal function, the transferred α -synuclein accumulates and leads to the formation of Lewy-like inclusions in cell models (Desplats et al , 2009 ).…”